Background and purpose:  The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis.

Experimental approach:  BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund's adjuvant or entrapped in poly(lactic acid‐glycolic acid) (PLGA) nanoparticles at different concentrations (1 µg, 5 µg, 10 µg, 20 µg or 40 µg·50 µL⁻¹). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines.

Key results:  Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non‐treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 µg·50 µL⁻¹) was more effective than ‘free’ P10 emulsified in Freund's adjuvant (20 µg·50 µL⁻¹), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 µg·50 µL⁻¹) were most effective. Treatment with P10 emulsified in Freund's adjuvant (20 µg·50 µL⁻¹) or P10 entrapped within PLGA (1 µg·50 µL⁻¹) were accompanied by high levels of interferon‐gamma in lung.

Conclusions and implications:  Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.